Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis

  • J Med Chem. 2023 Sep 14;66(17):12018-12032. doi: 10.1021/acs.jmedchem.3c00606.
Danni Rao  1  2 ,  Tao Yang  3  2 ,  Huixu Feng  4 ,  Qi An  4 ,  Shaofeng Zhang  4 ,  Jinghua Yu  5 ,  Xuelian Ren  6  2 ,  Xingxing Diao  5  2 ,  He Huang  6  4  2 ,  Wei Tang  3  2 ,  Shilin Xu  1  4  2
Affiliations
  • 1. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3. Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5. Center for Drug Metabolism and Pharmacokinetics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6. Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 37594408 DOI: 10.1021/acs.jmedchem.3c00606
Abstract

Psoriasis is a chronic inflammatory skin disease closely related with T cells, and its management remains a challenge. Novel targets and associated drugs are urgently needed. Zeta-chain-associated protein kinase 70 kDa (ZAP-70) has been recognized as a potential target for treating autoimmune diseases due to its crucial role in T cell receptor signaling. In our previous work, we identified a potent and selective covalent ZAP-70 inhibitor with anti-inflammatory activity in vitro. Herein, we report the structural optimization of covalent ZAP-70 inhibitors. Our efforts led to the discovery of compound 25 (RDN2150), which exhibited potent inhibitory activity against ZAP-70 and favorable selectivity. It also demonstrated promising inhibitory effects on T cell activation and inflammatory cytokine production. Furthermore, a topical application of 25 resulted in significant efficacy in an imiquimod-induced psoriasis mouse model. Overall, these findings present the basis of a promising strategy for the treatment of psoriasis by targeting ZAP-70.

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